Regulation of Iron Metabolism Harnish and Hariom Yadav NATIONAL AGRI FOOD BIOTECHNOLOGY INSTITUTE,MOHALI

OBJECTIVES  Processes involved in iron metabolism.  Role of HEPICIDIN.  Diseases caused by Hepicidin deficiency.

IRON METABOLISM  Dietary Iron: Iron is essential element and must be precisely regulated.  On the lumen side of small intestine iron is reduced from its ferric form(Fe 3+ ) to ferrous form(Fe 2+ ).  Ferrous iron is then transported in enterocytes by DMT1(divalent metal transporter).

 Iron can be either stored within the enterocyte as ferritin or it can be transferred across the basolateral membrane to the plasma by transport protein FERROPORTIN1 and MTP1. (Requires oxidation of Ferrous to Ferric by hephaestin.)

TRANSPORT PROTEINS  DMT1 (Divalent Metal Transporter 1) (Tranports from lumen into the enterocytes)  FERROPORTIN1 (Transports from enterocytes to circulation)

QUESTION????  Who is playing the central role in IRON METABOLISM??

ANSWER  HEPICIDIN is the key regulator of iron in our body.

What is HEPICIDIN??  Is a peptide hormone which was first identified in human urine and plasma in  Its molecular weight is 25 Kda.  Highly folded structure.  Present in inactive form;prohepcidin(60aa) and its active form is hepicidin(25aa).

HEPICIDN 25 Amino acid disulfide peptide.

Hepicidin, Primary regulator  Increased expression of hepicidin leads to Decrease iron absorption and release.  Mutation :Hemochromatosis  Increased expression:Iron deficiency  Hepicidin mRna expression is increased by erythropoetin,hypoxia & inflammation.  Also binds to ferroportin.

Ferroportin  The only cellular iron exporter in vertebrates.  Present in macrophages,placenta and the hepatocytes.

Mechanism of action of hepicidin  The major mechanism of hepicidin is THE REGULATION OF TRANSMEMBRANE IRON TRANSPORT.  It binds to FERROPORTIN,forms hepicidin- ferroportin complex,which is degraded in the lysosomes and iron is locked inside the cells(mainly enterocytes,hepatocytes and macrophages).

SO Hepcidin lowers iron absorption in the intestine,lowers iron releasing from hepatocytes and macrophages Serum iron is decreased.

Hepicidin Regulation So when hepicidin levels are low,iron exporting cells have abundant ferroportin and thus releases iron into plasma.When hepicidin concentration increases it binds to ferroportin and thus iron is retained in the cells.

Regulation of Hepicidin  Hypoxia/Anemia  Inflammation

Regulation of Hepcidin synthesis by anemia and hypoxia Oxygen Hepcidin Uptake of diet iron Iron release from hepatocytes Iron release from macrophages

Regulation of Hepcidin synthesis by inflammation  Interleukin-6 Hepcidin iron anemia of chronic disease.  Generally when iron level,ROS(Reactive oxygen species) that leads to in thiobarbutyric acid activation of NF Kappa proteins activates IL-6, hepicidin synthesis

Disease States  Hepcidin deficiency, physiological = Haemochromatosis  Hepcidin excess – anaemia of chronic disease

The role of Hepcidin in hereditary hemochromatosis Hereditary hemochromatosis: -excessive intestinal iron absorption -Saturation of transferrin -Iron deposition in vital organs

Overall summary Hepcidin -Is a recently discovered liver produced 25 amino-acid peptide -Is a regulator of iron metabolism that controls iron absorption and macrophage iron release. -Is regulated by erythropoietic needs( ),body iron stores( ) and inflammation( )